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Scientists Find Eye Pigment Controls Circadian Rhythm

Date:

May 28, 1998

Source:

University Of North Carolina At Chapel Hill

Summary:

University of North Carolina at Chapel Hill researchers have discovered a new light-sensitive pigment in the eye, the skin and part of the brain responsible for the body's internal clock. The discovery is the first of its kind in more than a century and might lead to better treatment for depressed people or fewer accidents at work during late-night shifts.

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CHAPEL HILL - University of North Carolina at Chapel Hill researchers have discovered a new light-sensitive pigment in the eye, the skin and part of the brain responsible for the body's internal clock. The discovery is the first of its kind in more than a century and might lead to better treatment for depressed people or fewer accidents at work during late-night shifts.

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The pigment, called cryptochrome or CRY, appears to control mammals' circadian rhythm, the 24-hour biological timer that regulates numerous bodily functions. Those processes -- synchronized to light and dark by light at dawn -- range from body temperature and blood pressure regulation to intellectual performance, sleeping and wakefulness.

"We are extremely excited about this fundamental discovery because it appears to be so central to mental and physiologic functioning," said Dr. Aziz Sancar, Kenan professor of biochemistry and biophysics at the UNC-CH School of Medicine. "In the past, it was assumed that the same pigment in the eye was responsible for both vision and circadian synchronization. We have now shown that that's not true."

A report on the findings appears in the May 26 issue of the Proceedings of the National Academy of Sciences, a scientific journal. Dr. Yasuhide Miyamoto, a postdoctoral fellow in biochemistry at UNC-CH, and Sancar, his mentor, wrote the report.

Discovered in 1877, pigments known as opsins, which are linked to vitamin A and located in the retina, enable mammals to see by absorbing light and transferring visual signals through the optic nerve to the brain, Sancar explained. The newly discovered cryptochromes, which come in two forms called CRY 1 and CRY 2, are linked to vitamin B-2 and located in a different part of the retina. Cryptochromes enable animals and humans to synchronize their circadian clock by absorbing blue light and transferring the light signal through the optic nerve to a different part of the brain from the center for vision.

Severing the optic nerve abolishes both vision and circadian photo-response, the scientist said. However, because pigments for vision and circadian clocks occur in different parts of the retina, some blind people who have lost the part of the retina containing opsins still retain the cryptochrome region and maintain normal circadian rhythm.

"Understanding how circadian rhythm works has many practical applications," said Sancar, a member of the UNC Lineberger Comprehensive Cancer Center. "First, individuals with a disease called seasonal affective disorder, or SAD, suffer serious depression during the winter months with short daylight. It may be that SAD patients have a defective gene that doesn't produce the pigment properly or simply suffer from a vitamin B-2 deficiency. Maybe we can treat some patients with vitamin B-2."

Second, industrial accidents such as those at Three Mile Island and Chernobyl often occur at night. American industry has collected data showing most accidents happen during the midnight shift.

"That's because people's circadian clocks have told them that it is time to slow down, and mistakes are more likely," Sancar said.

Jet lag follows the discrepancy between local time and a passenger's circadian time, which was in tune with the day and night cycle of the departure point. Also, breast cancer rates have climbed this century with some blaming long exposure to electric lights for disrupting normal hormone patterns.

Finally, he said, cancer experts also want to know more about such rhythms because both beneficial and side effects of anti-cancer drugs can depend on what time of day they are administered.

"For these and other reasons, understanding how the body's clock works, what its components are and how one can regulate it if necessary is very important," Sancar said.

In complex experiments on mice, he and Miyamoto found evidence of the new pigment widespread in body tissues including the skin.

A mouse, for example, sets its internal clock to the outside world through cryptochromes. To do that, it transmits light signals to genes that tell it how to respond physiologically to the time of day. Recently located "clock" genes have enabled scientists to begin learning how they work.

Daily light-dark cycles regulate biologic functions in creatures as simple as bacteria and as complex as humans, Sancar said. The new pigments are similar to a light-activated DNA repair mechanism found in bacteria and to blue-light photoreceptors that control plant growth.

Human Genome Project staff found the human CRY1 but not its function. Sancar and his students discovered the CRY2 gene in collaboration with Human Genome Sciences, Inc. researchers. They have applied for a patent on their work, which was supported by the National Institutes of Health.

"Dr. Sancar's discovery of novel photoreceptors that act to synchronize the body's internal clock to daily light and dark cycles is ground-breaking," said Dr. David Lee, chair of biochemistry and biophysics at UNC-CH. "Only rarely do scientists make observations that are of such fundamental importance. And since human health and well-being are intimately tied to normal cycling of the biological or circadian clock, his discovery has important, long-term implications."

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